What You Know That Ain’t Necessarily So: Glucosamine & Arthritis in Dogs

I recently gave a lecture at the Western Veterinary Conference called “What You Know that Ain’t Necessarily So.” The purpose of this was to take some common or controversial beliefs and practices in veterinary medicine and discuss the scientific evidence pertaining to these. This was not intended as a definitive, “final word” on these subjects, but as an illustration of how weak and problematic the evidence often is even behind widely held beliefs. In some cases, these practices or ideas may actually be valid, but without good quality scientific evidence, we should always be cautious and skeptical about them.

Eventually, I will post recordings of the presentations themselves, but for now I am posting a summary of each topic.

Each starts with a focused clinical question using the PICO format.

P– Patient, Problem Define clearly the patient in terms of signalment, health status, and other factors relevant to the treatment, diagnostic test, or other intervention you are considering. Also clearly and narrowly define the problem and any relevant comorbidities. This is a routine part of good clinical practice and so does not represent “extra work” when employed as part of the EBVM process.

I– Intervention Be specific about what you are considering doing, what test, drug, procedure, or other intervention you need information about.

C– Comparator What might you do instead of the intervention you are considering? Nothing is done in isolation, and the value of most of our interventions can only be measured relative to the alternatives. Always remember that educating the client, rather than selling a product or procedure, should often be considered as an alternative to any intervention you are contemplating.

O– Outcome What is the goal of doing something? What, in particular, does the client wish to accomplish. Being clear and explicit, with yourself and the client, about what you are trying to achieve (cure, extended life, improved performance, decreased discomfort, etc.) is essentially in evidence-based practice.

This is then followed by a summary of the evidence available at each of the levels in the following pyramid (which is a pragmatic reinterpretation of the classical pyramid of evidence that is a bit more useful for general practice veterinarians).

Finally, I list the Bottom Line, which is my interpretation of the evidence.

Glucosamine for Dogs with Arthritis

Clinical question

P– Dogs with naturally occurring arthritis

I– oral glucosamine

C– NSAID, nothing

O– Reduced pain, lameness

2. Synthetic Veterinary Literature

a. Three systematic reviews:

the global strength of evidence of efficacy was low…In addition, results were contradictory in the 2 studies conducted in dogs. (Vandeweerd et al., 2012)

Carprofen is superior to glucosamine/chondroitin supplements in reducing the clinical signs of osteoarthritis (McCarthy et al. 2007). Glucosamine and chondroitin supplement efficacy cannot be commented on, as there was no placebo group or there was no comparison made with the placebo group in the studies.

Despite some evidence that a combination of glucosamine hydrochloride and chondroitin sulfate nutraceuticals improves symptoms associated with joint disease in dogs and cats, strong clinical evidence of efficacy is lacking, and these compounds are understudied.

a. Systematic Reviews (dozens, these are just a few representative ones)

[Glucosamine] is ineffective for pain reduction in patients with knee OA. GS may have function-modifying effects in patients with knee OA when administered for more than 6 months. However, it showed no pain-reduction benefits after 6 months of therapy. (Wu, 2013)

Significant improvement in pain and functional indices and a decrease in the loss of joint space width were demonstrated in some but not all studies…The safety of these nutraceuticals has been demonstrated across all of the reviewed trials, and there were no significant issues with tolerance…An overall recommendation to use nutraceuticals in the treatment of all patients with OA is not strongly supported by the available data. (Ragle, 2012)

Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged. (Wandel, 2010)

Pooled results from studies using a non-Rotta preparation or adequate allocation concealment failed to show benefit in pain and WOMAC function while those studies evaluating the Rotta preparation showed that glucosamine was superior to placebo in the treatment of pain and functional impairment resulting from symptomatic OA. (Towheed, 2005)

Most of the observed heterogeneity in glucosamine trials is explained by brand…Large inconsistency was found though. Low risk of bias trials, using the Rottapharm|Madaus product, revealed a small effect size. (Eriksen, 2014)

b. Clinical Practice Guidelines

We cannot recommend using glucosamine and chondroitin for patients with symptomatic osteoarthritis of the knee…. At this time, both glucosamine and chondroitin sulfate have been extensively studied. Despite the availability of the literature, there is essentially no evidence that minimum clinically important outcomes have been achieved compared to placebo, whether evaluated alone or in combination. American Academy of Orthopedic Surgeons

We conditionally recommend that patients with OAshould not use the following:

Chondroitin sulfateGlucosamine

American College of Rheumatology

Glucosamine and chondroitin were both found to be “not appropriate” for all patients when used for disease modification and “uncertain” for all patients when used for symptom relief. Osteoarthritis Research Society International

Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo…. Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain.

At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo.

9 Responses to What You Know That Ain’t Necessarily So: Glucosamine & Arthritis in Dogs

I have an older dog with arthritis and we actually just started her on a higher quality GC and have actually noticed some improvements. I am a dietitian so research is very, very important to me and have been doing some investigating on the benefits of curcumin, boswellin, and bioperine for her arthritis but was wondering if you had any feedback on that combination supplement for dogs. I only seem to find isolated curcumin supplements or boswellin for dogs but not this combo and I want to ensure it’s safe for her. We currently give her boswellin but it doesn’t seem to be doing a whole lot. Any thoughts, please? Our current vet is very mainstream and isn’t able to help us much in this area.

I’m not aware of any controlled research on the combination. I have written about curcumin, and so far there isn’t much direct research evidence to show benefits. Some promising preliminary evidence exists, but nothing solid. There is far less evidence for Boswellia, so in general I’m not yet convinced that has much value.

This seems to show a pattern quite similar to other similar studies of nutraceutical for OA. All patients improve by a significant amount in the study, and the differences between the extent of improvement among treatment groups are much smaller than the effect of being in the study. This raises significant questions about how much real, meaningful impact the treatment had. For example, on a 100-point pain scale, the three groups showed the following improvement:

Placebo- 33.4 points
Chondroitin- 42.6 points
Celecoxib- 39.5 points

So the pain decreased an average of 40.5 points on a 100-point scale, but the differences between the groups were 6.1-9.2 points. That means the differences were pretty small compared to the overall improvement, suggesting just being in the trial contributed to most of the change. At most, the true underlying effect of the chondroitin would have been 9% better than nothing, which may be statistically significant but of questionable real-world significance.

Looked at another way, the minimum difference thought to have any clinical significance is 5 points, so technically a 9-point difference might be detectable by a patient. However, doing nothing except enrolling in the trial yielded 33-point difference, which is a LOT bigger! Perhaps just giving out placebos should be our first therapy for OA. 🙂

I also noticed that more people in the chondroitin group (39) and the placebo group (33) dropped out of the study than in the celecoxib group (27), which raises the question of whether subjects in those groups were more likley to drop out because they weren’t getting as much relief. And the number dropping out due to side effects from the drug was the same for chondroitin and celecoxib (8), which undermines the argument that chondroitin is better tolerated than NSAIDs.

It is possible that the chondroitin really did have as much effect and the celecoxib and that both were only barely more effective than placebo. If so, this seems more an indictment of the celecoxib than a validation of the use of chondroitin since NSAIDs usually perform better than this against placebo. In a meta-analysis, for example, celecoxib was on average 17% better than placebo (0.86 on a 5-point scale), which is almost three times the difference in this study (6.1% or 6.1 points on a 100-point scale). It makes one wonder about the accuracy of assessment or the effectiveness of the positive comparator inthis study.

I still struggle to reconcile the evidence with my experience with my older dog, who started on a supplement after diagnosis of mild OA and a short course of NSAIDs. It was two years before her condition worsened enough to need NSAIDs again. I understand this can be explained but I do wonder if future studies may find a benefit.

Are you aware of any studies that look at the impact of glucosamine and chondroitin on joint health and disease prevention, as opposed to treatment of OA? I wondered if there could be some benefit in slowing cartilage degeneration, but most studies I’m aware of tend to focus on treating OA. Aware there is much more complexity in this kind of longitudinal study, so I assume it’s unlikely, but thought you would know!

Lots of research in humans, not much in dogs. Overall, the dog research is unconvincing. The human research is mixed, but it’s been hard to find any consistent, meaningful benefits despite decades of research in thousands of people, which doesn’t seem cause for much optimism. Here are some of the most recent reviews:

Clin Exp Rheumatol. 2018 Jan 31. [Epub ahead of print]
Comparative effectiveness of glucosamine, chondroitin, acetaminophen or celecoxib for the treatment of knee and/or hip osteoarthritis: a network meta-analysis.
Zhu X1, Wu D1, Sang L2, Wang Y2, Shen Y3, Zhuang X2, Chu M2, Jiang L4.
Author information
Abstract
OBJECTIVES:
To compare the efficacies of oral glucosamine, chondroitin, the combination of glucosamine and chondroitin, acetaminophen and celecoxib on the treatment of knee and/or hip osteoarthritis.
METHODS:
We searched electronic databases including PubMed, Embase, and Cochrane Library and the reference lists of relevant articles published from inception to October 23, 2017. A Bayesian hierarchical random effects model was used to examine the overall effect size among mixed multiple interventions.
RESULTS:
We identified 61 randomised controlled trials of patients with knee and/or hip osteoarthritis. There was no obvious difference in the results between the traditional meta-analysis and the network meta-analysis. The network meta-analysis demonstrated that celecoxib was most likely the best option (SMD, -0.32 [95% CI, -0.38 to -0.25]) for pain, followed by the combination of glucosamine and chondroitin. For physical function, all interventions were significantly superior to oral placebo except for acetaminophen. In terms of stiffness, glucosamine(SMD, -0.36 [95% CI, -0.67 to -0.06]) and celecoxib (SMD, -0.29 [95% CI, -0.51 to -0.08]) were significantly better compared to placebo. In view of safety, compared to placebo only, celecoxib and acetaminophen presented significant differences.
CONCLUSIONS:
Given the effectiveness of these non-steroidal anti-inflammatory drugs and symptomatic slow-acting drugs, oral celecoxib is more effective than placebo on relieving pain and improving physical function, followed by the combination of glucosamine and chondroitin. Acetaminophen is likely the least efficacious intervention option. This information, accompanied by the tolerability and economic costs of the included treatments, would be conducive to making decisions for clinicians.

Ann Rheum Dis. 2017 Nov;76(11):1862-1869. doi: 10.1136/annrheumdis-2017-211149. Epub 2017 Jul 28.
Subgroup analyses of the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic review and individual patient data meta-analysis from the OA trial bank.
Runhaar J1, Rozendaal RM1, van Middelkoop M1, Bijlsma HJW2, Doherty M3, Dziedzic KS4, Lohmander LS5, McAlindon T6, Zhang W3, Bierma Zeinstra S7.
Author information
Abstract
OBJECTIVE:
To evaluate the effectiveness of oral glucosamine in subgroups of people with hip or knee osteoarthritis (OA) based on baseline pain severity, body mass index (BMI), sex, structural abnormalities and presence of inflammation using individual patient data.
METHODS:
After a systematic search of the literature and clinical trial registries, all randomised controlled trials (RCTs) evaluating the effect of any oral glucosamine substance in patients with clinically or radiographically defined hip or knee OA were contacted. As a minimum, pain, age, sex and BMI at baseline and pain as an outcome measure needed to be assessed.
RESULTS:
Of 21 eligible studies, six (n=1663) shared their trial data with the OA Trial Bank. Five trials (all independent of industry, n=1625) compared glucosamine with placebo, representing 55% of the total number of participants in all published placebo-controlled RCTs. Glucosamine was no better than placebo for pain or function at short (3 months) and long-term (24 months) follow-up. Glucosamine was also no better than placebo among the predefined subgroups. Stratification for knee OA and type of glucosamine did not alter these results.
CONCLUSIONS:
Although proposed and debated for several years, open trial data are not widely made available for studies of glucosaminefor OA, especially those sponsored by industry. Currently, there is no good evidence to support the use of glucosamine for hip or knee OA and an absence of evidence to support specific consideration of glucosamine for any clinically relevant OA subgroup according to baseline pain severity, BMI, sex, structural abnormalities or presence of inflammation.

Int J Clin Pract. 2013 Jun;67(6):585-94. doi: 10.1111/ijcp.12115.
Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials.
Wu D1, Huang Y, Gu Y, Fan W.
Author information
Abstract
OBJECTIVE:
To determine the efficacies of different preparations of glucosamine for the treatment of osteoarthritis (OA).
METHODS:
Systematic searches of the bibliographic databases Medline, Embase, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews for randomised, double-blind, placebo-controlled trials (RCTs) concerning glucosamine treatment of OA. Effect size (ES) was estimated using Cohen’s standardised mean difference. Consistency was evaluated via the I(2) index.
RESULTS:
Nineteen trials (3159 patients) contributed to the meta-analysis, revealing a large degree of inconsistency among the trials in terms of pain-reduction outcome: the combined ES in glucosamine sulphate (GS) trials was -0.22 [95% confidence intervals (CI) -0.48, 0.04], I(2) was 82.3%. The combined ES in glucosamine hydrochloride (GH) trials was -0.03 (95% CI -0.14, 0.08), with an absence of heterogeneity. No treatment ES was observed [-0.38 (95% CI -0.99, 0.23)] favouring GS in trials of less than 24 weeks duration and the I(2) remained high (I(2) = 88.5%). No significant treatment ES -0.09 (95% CI -0.21, 0.03) was observed in trials of more than 24 weeks duration compared with placebo, with a heterogeneity of zero. In terms of function-modifying outcomes, GS showed no significant effect on Lequesne Index reduction vs. placebo in trials of less than 24 weeks duration (ES -0.55 (95% CI -1.22, 0.11)) with a high degree of heterogeneity (I(2) = 92.9%). Pooling data from studies with durations of more than 24 weeks presented a significant combined ES of -0.36 (95% CI: -0.56, -0.17) with an absence of heterogeneity. No risk of publication bias could be detected using Egger test.
CONCLUSIONS:
GH is ineffective for pain reduction in patients with knee OA. GS may have function-modifying effects in patients with knee OA when administered for more than 6 months. However, it showed no pain-reduction benefits after 6 months of therapy.

Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827.
Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee.
Zeng C1, Wei J2,3, Li H1, Wang YL1, Xie DX1, Yang T1, Gao SG1, Li YS1, Luo W1, Lei GH1.
Author information
Abstract
This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA.
BMJ. 2010 Sep 16;341:c4675. doi: 10.1136/bmj.c4675.
Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
Wandel S1, Jüni P, Tendal B, Nüesch E, Villiger PM, Welton NJ, Reichenbach S, Trelle S.
Author information
Abstract
OBJECTIVE:
To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee. Design Network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points.
MAIN OUTCOME MEASURE:
Pain intensity. Secondary outcome was change in minimal width of joint space. The minimal clinically important difference between preparations and placebo was prespecified at -0.9 cm on a 10 cm visual analogue scale.
DATA SOURCES:
Electronic databases and conference proceedings from inception to June 2009, expert contact, relevant websites. Eligibility criteria for selecting studies Large scale randomised controlled trials in more than 200 patients with osteoarthritis of the knee or hip that compared glucosamine, chondroitin, or their combination with placebo or head to head. Results 10 trials in 3803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was -0.4 cm (95% credible interval -0.7 to -0.1 cm) for glucosamine, -0.3 cm (-0.7 to 0.0 cm) for chondroitin, and -0.5 cm (-0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P=0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero. Conclusions Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged.

Rheumatol Int. 2010 Jan;30(3):357-63. doi: 10.1007/s00296-009-0969-5. Epub 2009 Jun 21.
Effect of glucosamine or chondroitin sulfate on the osteoarthritis progression: a meta-analysis.
Lee YH1, Woo JH, Choi SJ, Ji JD, Song GG.
Author information
Abstract
The aim of this study was to assess the structural efficacies of daily glucosamine sulfate and chondroitin sulfate in patients with knee osteoarthritis (OA). The authors surveyed randomized controlled studies that examined the effects of long-term daily glucosamine sulfate and chondroitin sulfate on joint space narrowing (JSN) in knee OA patients using the Medline and the Cochrane Controlled Trials Register, and by performing manual searches. Meta-analysis was performed using a fixed effect model because no between-study heterogeneity was evident. Six studies involving 1,502 cases were included in this meta-analysis, which consisted of two studies on glucosamine sulfate and four studies on chondroitin sulfate. Glucosamine sulfate did not show a significant effect versus controls on minimum JSN over the first year of treatment (SMD 0.078, 95% CI -0.116 to -0.273, P = 0.429). However, after 3 years of treatment, glucosamine sulfate revealed a small to moderate protective effect on minimum JSN (SMD 0.432, 95% CI 0.235-0.628, P < 0.001). The same was observed for chondroitin sulfate, which had a small but significant protective effect on minimum JSN after 2 years (SMD 0.261, 95% CI 0.131-0.392, P < 0.001). This meta-analysis of available data shows that glucosamine and chondroitin sulfate may delay radiological progression of OA of the knee after daily administration for over 2 or 3 years.
Arthritis Care Res (Hoboken). 2014 Dec;66(12):1844-55. doi: 10.1002/acr.22376.
Risk of bias and brand explain the observed inconsistency in trials on glucosamine for symptomatic relief of osteoarthritis: a meta-analysis of placebo-controlled trials.
Eriksen P1, Bartels EM, Altman RD, Bliddal H, Juhl C, Christensen R.
Author information
Abstract
OBJECTIVE:
To determine whether study sponsor, chemical formulation, brand of glucosamine, and/or risk of bias explain observed inconsistencies in trials of glucosamine's efficacy for treating pain in osteoarthritis (OA).
METHODS:
A systematic review and stratified meta-analysis of randomized placebo-controlled trials was performed, and random-effects models were applied with inconsistency (I(2) ) and heterogeneity (tau(2) ) estimated using Review Manager and SAS, respectively. The major outcome was reduction of pain; the standardized mean difference (SMD [95% confidence interval (95% CI)]) served as effect size.
RESULTS:
The inclusion criteria yielded 25 trials (3,458 patients). Glucosamine moderately reduced pain (SMD -0.51 [95% CI -0.72, -0.30]), although a high level of between-trial inconsistency was observed (I(2) = 88%). The single most important explanation (i.e., covariate) was brand, reducing heterogeneity by 41% (P = 0.00032). Twelve trials (1,437 patients) using the Rottapharm/Madaus product resulted in significant pain reduction (SMD -1.07 [95% CI -1.47, -0.67]), although a sensitivity analysis of 3 low risk of bias trials using the Rottapharm/Madaus product showed less promising results (SMD -0.27 [95% CI -0.43, -0.12]), which is only a small effect size. Thirteen trials (1,963 patients) using non-Rottapharm/Madaus products consistently failed to show a reduction in pain (SMD -0.11 [95% CI -0.46, 0.24]). The second most important explanation was overall risk of bias (reducing heterogeneity by 32%).
CONCLUSION:
Most of the observed heterogeneity in glucosamine trials is explained by brand. Trials using the Rottapharm/Madaus glucosamine product had a superior outcome on pain in OA compared to other preparations of glucosamine. Large inconsistency was found, however. Low risk of bias trials, using the Rottapharm/Madaus product, revealed a small effect size.

What is the deal with Neurontin/gabapentin being prescribed for mild/moderate arthritic pain in dogs. Less side effects than NSAIDS but does it work?
My small breed is 5 years old and had an odd gait when I got him, he was a little less than 1 year old, pediatric neuter and had been cooped up in a pen.
He responded well to slow but steady walks (up to 4-5 miles)
Lately he has begun to limp once or twice a week for a day (tends to favor and not put weight on one hind leg) if he walks more than 2 miles.
If I don’t walk him he is better in about 2 days, then it all starts again.
Should I opt for x-rays, additional testing? Or, aqua therapy once a twice a week (if I can afford it) and prn Neurontin?
I had him looked at a while back, hips okay, no anomalies observed.
I was advised if it got worse to go for additional diagnostic testing.
However, He has an excellent appetite and will break into a full trot if he sees a squirrel…….so maybe he is not that uncomfortable?

Tried the glucosamine on the recommendation of my vet. Sure enough 2-3 weeks in the possible side effect of GI upset, vomiting began. Pretty sure the glucosamine is the culprit. Hoping symptoms will resolve within a day or two…..